Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

• This invention relates to the use of certain quinolyl- and isoquinolyloxazole-2-ones in the treatment and prevention of infections by enveloped virus including retroviral, e.g., HIV, infections.
• Retroviruses are a class of ribonucleic acid (RNA) viruses that replicate by using reverse transcriptase to form a strand of complementary DNA (cDNA) from which a double stranded,proviral DNA is produced. This proviral DNA is then randomly incorporated into the chromasomal DNA of the host cell making possible viral replication by later translation of the integrated DNA containing the viral genome.
• RNA ribonucleic acid
• retroviruses are oncogenic or tumor causing. Indeed the first two human retroviruses discovered, denoted human T-cell leukemia virus I and II or HTLV-I and II, were found to cause rare leukemias in humans after infection of T-lymphocytes. The third such human virus to be discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes, specifically the CD4+ subpopulation, and has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC).
• AIDS acquired immune deficiency syndrome
• ARC AIDS related complex
• Retroviruses have, in addition to the usual viral capsid, an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed the lipid of the retroviral membrane is probably derived directly from the membrane of a previously infected host cell, however, the glycoprotein of the viral membrane is unique to the virus itself and is coded for by the viral genome. Infection of a host cell by a retrovirus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus.
• the glycoprotein envelope of the retroviruses plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes.
• viruses are coated or enveloped by a glycoprotein layer as well.
• viruses include the herpes simplex viruses (HSV), the influenza viruses, cytomegloviruses (CMG), and others.
• Applicants have determined that certain quinolyl- and isoquinolyloxazole-2-ones having PKC inhibiting activity are useful in the treatment of various enveloped virus infections including in the treatment of AIDS and ARC resulting from infection by HIV or other retroviruses.
• the present invention is directed to the use of certain quinolyl- and isoquinolyloxazole-2-ones of the formula wherein R and R1 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and phenyl or C1-C3 alkylphenyl wherein the phenyl ring is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C1-C4 alkyl, and C1-C4 alkoxy; and R2 is a 2-, 3-, or 4-quinolyl group or a 1-, 3-, or 4-­isoquinolyl group wherein the quninolyl or isoquinolyl group is optionally substituted with one, two or three of the substituents selected from the group consisting of fluorine, chlorine, bromine, C1-C4 alkyl, C1-C4 alkoxy, nitro, trifluoromethyl, and phenyl optionally substituted with one, two
• This invention concerns the use of the compounds of Formula I as agents effective in the treatment of infections of enveloped viruses.
• C1-C3 alkyl mean straight or branched chain alkyl groups having from one to three, from one to four, or from one to six carbon atoms respectively, and include such groups as methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec -butyl, tert -­butyl, and the like, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, and the like.
• C1-C4 alkoxy means alkoxy groups having from one to four carbon atoms, and includes such groups as methoxy, ethoxy, n -­propoxy, isopropoxy, n -butoxy, isobutoxy, sec -butoxy, tert -­butoxy, and the like.
• R or R1 is "optionally substituted C1-C3 alkylphenyl"
• the one, two or three substituent(s) can be located at any available position on the phenyl ring.
• R2 is 2-, 3-, or 4-quinolyl or 1-, 3-, or 4-isoquinolyl
• the optional substituent(s) can be located at any available position(s) on the quinolyl or isoquinolyl ring.
• a pharmaceutically acceptable acid addition salt is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acids and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
• Illustrative organic acids which form suitable salts include the mono, di, and tricarboxylic acids.
• Such acids are,for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, and 2-phenoxybenzoic acids.
• Other organic acids which form suitable salts are the sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
• the acid salts are prepared by standard techniques such as by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvent containing the appropriate acid and isolating by evaporating the solution, or by reacting the free base in an organic solvent in which case the salt separates directly or can be obtained by concentration of the solution.
• the acid addition salts of the compounds of this invention are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility.
• isoquinolyl derivatives are also intended. As is true for most classes of therapeutically effective compounds, certain subclasses and certain species which are especially effective are preferred over others. In this instance, those compounds of Formula I wherein R2 is optionally substituted 2-, 3-, or 4-quinolyl are preferred. Also preferred are compounds wherein R is C1-C6 alkyl, as well as compounds wherein R1 is hydrogen. Most preferred are the compounds wherein R2 is an unsubstituted 2-, 3-, or 4-quinolyl group, R is ethyl or propyl and R1 is hydrogen.
• Reaction Scheme 1 illustrates that the 2-, 3-, or 4-quinolyloxazole-2-ones of Formula I can be prepared by reacting the appropriate and readily available 2-, 3-, or 4-­quinoline carboxaldehyde (II) in tetrahydrofuran (THF) with alkylmagnesium chloride or with optionally substituted phenylalkyl-magnesium chloride (RMgCl] to produce 2-, 3-, or 4-­quinoline alkanol (III), which is in turn oxidized with oxalyl chloride (ClCOCOCl), methyl sulfoxide [(CH3)2SO] and triethylamine (Et3N) in dichloromethane (CH2Cl2) to produce quinolyl-alkanone (IV).
• the alkanone (IV) can alternately be brominated to compound (VIII a ) and further treated with triethylamine in dimethylformamide (DMF) in the presence of potassium cyanate (KCNO) to form the compounds of Formula I according to procedures well known in the art and illustrated in the examples herein; or compound IV can be converted to oxime (V) by refluxing with hydroxylamine hydrochloride (H2NOH ⁇ HCl) and pyridine in ethanol (EtOH). Compound (V) is then reacted with p-toluenesulfonyl chloride and triethylamine in dichloromethane to produce compound (VI).
• DMF dimethylformamide
• KCNO potassium cyanate
• the amine (VII) is then produced by reacting compound (VI) with sodium ethoxide in ethanol (NaOEt/EtOH), followed by ether and aqueous hydrochloric acid (HCl) extraction.
• the amine (VII) is further reacted with 1,1′-carbonyldiimidazole at about 0°C to form compound (VIII b ), which is then heated to about 170°C to yield the appropriate 2-, 3-, or 4-quinolyloxazole-2-ones of Formula I.
• Reaction Scheme 2 illustrates that the 5-, 6-, 7-, or 8-quinolyloxazole-2-ones of Formula I can be prepared in essentially the same manner as described for Reaction Scheme 1.
• the alkanone starting material (IX) is prepared by metalating 5-, 6-, 7- or 8-bromoquinoline according to a procedure by H. Gilman and T. Suddy set forth in J. Org. Chem. 23 , 1584-9 (1958), and then reacting it with N-alkoxy-N-alkylamides.
• the 5-, 6-, 7-, or 8-bromoquinoline compounds are prepared by following procedures set forth in "The Chemistry of Heterocyclic Compounds" by Gurnos Jones, as found in Quinolines , Part 1, vol.
• the formula (IV) and formula (IX) compounds of Reaction Schemes 1 or 2 can also be prepared by reacting the appropriate bromoquinoline with butyl lithium in an appropriate solvent such as THF or diethyl ether at -70°C to 0°C, preferably at -50°C, and then reacting the lithiated compound with wherein R is as described in Formula I. This reaction is further specifically exemplified in Example 8.
• Compound (XIV) can be prepared by a procedure set forth in Tetrahedron Letters , 22 , 3815 (1981).
• R1 is C1-C6 alkyl or optionally substituted C1-C3 alkylphenyl are produced by subsequent reaction of the compound of Formula I of either Reaction Scheme 1 or Reaction Scheme 2 with sodium hydride and the appropriate alkyl iodide or phenylalkyl iodide in tetrahydrofuran according to procedures well known in the art.
• oxazolone derivatives of this invention act as anti-enveloped virus agents can be demonstrated by their ability to inhibit the growth and replication of murine leukemia virus, an oncogenic retrovirus, as determined by an in vitro XC plaque assay.
• This assay was performed according to the method of Rowe et al . ( Virology , 1970, 42 , 1136-39) as previously described by L. Hsu, et al . ( J. Virological Methods , 1980, 1 , 167-77) and T. L. Bowlin and M. R. Proffitt ( J. Interferon Res. , 1983, 3(1) , 19-31).
• Mouse SC-1 cells (fibroblast) (105) were seeded into each well of 6-well cluster plates (Costar #3506) in 4 ml Minimum Essential Medium (MEM) with 10% Fetal Calf Serum (FCS). Following an 18 hour incubation period (37°C), Moloney murine leukemia virus (MoLV) was applied at a predetermined titer to give optimal (i.e. countable) numbers of virus plaques. Compounds were added 2 hours prior to addition of the virus. Three days later the culture medium was removed, the SC-1 cell monolayers were exposed to UV irradiation (1800 ergs), and rat XC cells (106) were seeded into each well in 4 ml MEM.
• MEM Minimum Essential Medium
• FCS Fetal Calf Serum
• the ability of the oxazolone derivatives of this invention to act as anti-enveloped virus agents can be demonstrated by their ability to reduce expression of p24 antigen from HIV infected T-lymphocytes.
• Cells (C8166 T cell line) were pretreated with test compounds at appropriate concentrations for 3 hours prior to virus (RF strain of HIV-1) absorption. Low multiplicity of infection was used and virus absorption period was 1 hour at room temperature. the cells were washed X1 in PBS and resuspended in fresh medium containing the appropriate concentrations of test compound. Cells incubated at 37°C and after 3 days culture fluid was assayed for p24 antigen as a measure of viral replication.
• the oxazolone derivatives of this invention can be used to treat a number of diseases and conditions known to be caused by enveloped viruses including those diseases and conditions caused by murine leukemia virus, feline leukemia virus, cytomegalovirus (CMV), avian sarcoma virus, herpes simplex virus (HSV), invluenza virus, human immunodeficiency virus (HIV), HTLV-Z, and HTLV-II.
• CMV murine leukemia virus
• CMV cytomegalovirus
• HSV herpes simplex virus
• HIV human immunodeficiency virus
• HTLV-Z human immunodeficiency virus
• HTLV-II HTLV-II
• the amount of the oxazolone derivative of formula 1 to be administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular oxazolone derivative selected. Moreover the oxazolone derivative can be used in conjunction with other agents known to be useful in the treatment of enveloped virus diseases and agents known to be useful to treat the symptoms of and complications associated with diseases and conditions caused by enveloped viruses.
• the anti-enveloped virally effective amount of a oxazolone derivative of formula 1 to be administered will generally range from about 15 mg/kg to 500 mg/kg.
• a unit dosage may contain from 25 to 500 mg of the oxazolone derivative, and can be taken one or more times per day.
• the oxazolone derivative can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally or parenterally.
• the preferred route of administration is oral administration.
• the oxazolone derivative can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions.
• the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and cornstarch.
• the compounds of this invention can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
• conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin
• disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch,
• Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent, or emulsifying agent.
• diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent, or emulsifying agent.
• oxazolone derivatives of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethylene-glycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such
• Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
• Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
• Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-­aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
• suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides
• compositions of this invention will typically contain from about 0.5 to about 25% by weight of the oxazolone derivative of formula 1 in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-­ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight.
• the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
• surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
• polyethylene sorbitan fatty acid esters for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
• Triethylamine (35.6 ml) was then added and the mixture was allowed to stir cold for about 1 hour. After the mixture had been allowed to warm to room temperature, it was poured into a flask containing about 600 ml water. The CH2Cl2 layer was separated and the aqueous layer extracted with CH2Cl2 (2 times, 100 ml each). The combined CH2Cl2 layers were washed with saturated sodium chloride and dried over magnesium sulfate. The inorganic matter was filtered off and the solvent evaporated leaving a residue that was flash chromatographed as in Example 1. Evaporation left 9.0 grams of title compound.
• Example 5 The compound of Example 5 (19.8 grams) was dissolved in about 300 ml water, and the solution filtered by gravity into a 1 liter, 3-necked flask equipped with a mechanical stirrer and a thermometer. The solution was cooled to 0°C with stirring in an ice/methanol bath, and 29.87 grams (0.185 M) 1,1′-­carbonyldiimidazole was added over a 5 minute period. The mixture was allowed to stir cold for about 15 minutes. The resulting precipitate was taken up in about 500 ml ethyl acetate and separated from the water. The solution was washed with saturated sodium chloride and dried over magnesium sulfate, and the inorganic matter filtered off using diatomaceous earth under vacuum. The solvent was evaporated leaving the title compound.
• Example 6 The compound of Example 6 (12 grams) was heated under vacuum to 170°C for about 30 minutes, allowed to cool to room temperature and washed with water. The water was decanted and the residue was treated with CH2Cl2 (20 ml). The CH2Cl2 was evaporated leaving 7.8 grams of residue. The product was purified by means of flash chromatography on silica, eluting with ethyl acetate. The solvent was evaporated and the residue dissolved in 48 ml hot 50% ethanol, filtered and allowed to cool to room temperature. The precipitate was collected by vacuum filtration and dried in vacuo at 78°C, leaving 1.97 grams (21%) title compound. M.p. 188-190°C dec.; analysis calced. for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02; analysis found: C, 71.10; H, 5.73; N, 10.76.
• n-butyl lithium (0.0025 M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60°C to -55°C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-N-methoxybutyramide were then added dropwise at -50°C and the solution was stirred an additional 30 minutes. The solution was then allowed to warm to 0°C and stirred for one hour.
• EXAMPLE 9 A tablet is prepared from 4-Methyl-5-(3-quinolinyl)-1-(3H)-oxazolone 250 mg Starch 40 mg Talc 10 mg Magnesium 10 mg EXAMPLE 10 A capsule is prepared from 4-phenyl-5-(2-quinolinyl)-1-(3H)-oxazolone 400 mg Talc 40 mg Sodium Carboxymethy celulose 40 mg Starch 120 mg
• compositions which are comprised of an inert carrier and an effective amount of a compound of Formula I, or a salt thereof.
• An inert carrier is any material which does not interreact with the compound to be carried and which lends support, means of conveyance bulk, traceable material, and the like to the compound to be carried.
• An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

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• 1990
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